The invention pertains to the discovery and use of new compounds that inhibit the enzymatic activity of picornaviral 3C proteases, specifically rhinovirus proteases (RVPs), as well as retard viral growth in cell culture.
The picornaviruses are a family of tiny non-enveloped positive stranded RNA containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, menigovirus, foot and mouth viruses, hepatitis A virus and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies to cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picomaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective, small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
The present invention is directed to compounds that function as picornaviral 3C protease inhibitors, particularly those that have antiviral activity. It is further directed to the use of such 3C protease inhibitors. The Inventors demonstrate that the compounds of the present invention bind to rhinovirus 3C proteases and preferably have antiviral cell culture activity. The enzymatic inhibition assays used reveal that these compounds can bind irreversibly, and the cell culture assays demonstrate that these compounds can possess anti-viral activity.
The present invention is directed to compounds of the formula (I): 
wherein:
M is O or S;
R1 is H, F, an alkyl group, OH, SH, or an O-alkyl group;
R2 and R5 are independently selected from H, 
or an alkyl group, wherein the alkyl group is different from 
with the proviso that at least one of R2 or R5 must be 
and wherein, when R2 or R5 is 
X is xe2x95x90CH or xe2x95x90CF and Y1 is xe2x95x90CH or xe2x95x90CF,
or X and Y1 together with Q1 form a three-membered ring in which Qxe2x80x2 is xe2x80x94C(R10)(R11)xe2x80x94 or xe2x80x94Oxe2x80x94, X is xe2x80x94CHxe2x80x94 or xe2x80x94CFxe2x80x94, and Y1 is xe2x80x94CHxe2x80x94, xe2x80x94CFxe2x80x94, or xe2x80x94C(alkyl)-, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is xe2x80x94CH2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94CHFxe2x80x94, or xe2x80x94Sxe2x80x94, and Y1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR12xe2x80x94, xe2x80x94C(R13)(R14)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, or xe2x80x94C(CR13R14)xe2x80x94,
wherein R12 is H or alkyl, and R13 and R14 independently are H, F, or an alkyl group, or, together with the atoms to which they are bonded, form a cycloalkyl group or a heterocycloalkyl group;
A1 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), Pxe2x80x94OR15, or Pxe2x80x94NR15R16,
wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
D1 is a moiety with a lone pair of electrons capable of forming a hydrogen bond; and
B1 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18,
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
and with the provisos that when D1 is the moiety xe2x89xa1N with a lone pair of electrons capable of forming a hydrogen bond, B1 does not exist; and when A1 is an sp3 carbon, B1 is not xe2x80x94NR17R18 when D1 is the moiety xe2x80x94NR25R26 with a lone pair of electrons capable of forming a hydrogen bond, wherein R25 and R26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
and wherein D1-A1-B1 optionally forms a nitro group where A1 is N;
and further wherein, when R2 or R5 is 
X is xe2x95x90CH or xe2x95x90CF and Y2 is xe2x95x90C, xe2x95x90CH, or xe2x95x90CF,
or X and Y2 together with Qxe2x80x2 form a three-membered ring in which Qxe2x80x2 is xe2x80x94C(R10)(R11)xe2x80x94 or xe2x80x94Oxe2x80x94, X is xe2x80x94CHxe2x80x94 or xe2x80x94CFxe2x80x94, and Y2 is xe2x80x94CHxe2x80x94, xe2x80x94CFxe2x80x94, or xe2x80x94C(alkyl)-, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is xe2x80x94CH2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94CHFxe2x80x94, or xe2x80x94Sxe2x80x94, and Y2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Rxe2x80x212)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(Rxe2x80x213)Rxe2x80x214)xe2x80x94, xe2x80x94C(S)xe2x80x94, or xe2x80x94C(CRxe2x80x213Rxe2x80x214)xe2x80x94,
wherein Rxe2x80x212 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94ORxe2x80x213, xe2x80x94NRxe2x80x213Rxe2x80x214, xe2x80x94C(O)xe2x80x94Rxe2x80x213, xe2x80x94SO2Rxe2x80x213, or xe2x80x94C(S)Rxe2x80x213, and Rxe2x80x213 and Rxe2x80x214, independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
A2 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), Pxe2x80x94OR15, or Pxe2x80x94NR15R16,
wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are bonded, form a heterocycloalkyl group;
D2 is a moiety with a lone pair of electrons capable of forming a hydrogen bond; and
B2 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18,
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
xe2x80x83and further wherein any combination of Y2, A2, B2, and D2 forms a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
R3 and R6 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94C(O)R17, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18,
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
or, R3 and R6, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
R7 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18,
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
or R7, together with R3 or R6 and the atoms to which they are attached, form a heterocycloalkyl group;
R20 is H, OH, or any suitable organic moiety; and
Z and Z1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94PO(OR21)2, xe2x80x94PO(R21)(R22), xe2x80x94PO(NR21R22)(OR23), xe2x80x94PO(NR21R22(NR23R24), xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23,
wherein R21, R22, R23, and R24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
or Z1, as defined above, together with R1, as defined above, and the atoms to which Z1 and R1 are bonded, form a cycloalkyl or heterocycloalkyl group,
or Z and Z1, both as defined above, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;
and pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates thereof, and wherein these compounds, pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates preferably have antipicornaviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay, and more preferably antirhinoviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay and/or anticoxsachieviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay.
The present invention relates to compounds of the formula I: 
wherein R1, R2, R3, R5, R6, R7, R20, M, Z, and Z1 are as defined above, and to the pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates thereof, where these compounds, pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates preferably have antipicornaviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay, and more preferably antirhinoviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay and/or anticoxsachieviral activity with an EC50 less than or equal to 10 xcexcM in the HI-HeLa cell culture assay.
The present invention preferably relates to compounds of the formula X: 
wherein:
R61 is H, F, or an alkyl group;
R62 is selected from one of the following moieties: 
wherein:
R35 is H, an alkyl group, an aryl group, xe2x80x94OR38, or xe2x80x94NR38R39,
wherein R38 and R39 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group; and
R36 is H or an alkyl group,
or R35 and R36, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group or a heteroaryl group;
R37 is an alkyl group, an aryl group, or xe2x80x94NR38R39, wherein R38 and R39 are as defined above;
R50 is H, an alkyl group, an aryl group, xe2x80x94OR38, xe2x80x94SR39, xe2x80x94NR38R39, xe2x80x94NR40NR38R39, or xe2x80x94NR38OR39, or R50 and R36, together with the atoms to which they are attached, form a heterocycloalkyl group;
wherein R38 and R39 are as defined above and R40 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group; and
n is 0, 1, or 2;
R63 is H or an alkyl group;
R64 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
R65 is H or an alkyl group;
R66 is H, an acyl group, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a sulfonyl group, or a heteroaryl group;
R67 is H or an alkyl group; and
Z and Z1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94PO(OR21)2, xe2x80x94PO(R21)(R22), xe2x80x94PO(NR21R22)(OR23), xe2x80x94PO(NR21R22)(NR23R24), xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23,
wherein R21, R22, R23, and R24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group,
or Z and Z1, both as defined above, together with the atoms to which they are attached, form a heterocycloalkyl group;
and pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates thereof.
As used in the present application, the following definitions apply:
An xe2x80x9calkyl groupxe2x80x9d is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to the following moieties: 
An xe2x80x9caryl groupxe2x80x9d is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, the following moieties: 
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, the following moieties: 
An xe2x80x9cacyl groupxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, wherein R is any suitable substituent as defined below.
A xe2x80x9cthioacyl groupxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, wherein R is any suitable substituent as defined below.
A xe2x80x9csulfonyl groupxe2x80x9d is intended to mean a xe2x80x94SO2R radical, wherein R is any suitable substituent as defined below.
The term xe2x80x9csuitable substituentxe2x80x9d is intended to mean any of the substituents recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, hydroxy groups, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroarlyoxy groups, arylthio groups, heteroarylthio groups, and the like.
The term xe2x80x9csuitable organic moietyxe2x80x9d is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxy groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
A xe2x80x9chydroxy groupxe2x80x9d is intended to mean the radical xe2x80x94OH.
An xe2x80x9camino groupxe2x80x9d is intended to mean the radical xe2x80x94NH2.
An xe2x80x9calkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NHR where R is an alkyl group as defined above.
A xe2x80x9cdialkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NRaRb where Ra and Rb are each independently an alkyl group as defined above.
An xe2x80x9calkoxy groupxe2x80x9d is intended to mean the radical xe2x80x94OR where R is an alkyl group as defined above, for example, methoxy, ethoxy, propoxy, and the like.
An xe2x80x9calkoxycarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)OR where R is an alkyl group as defined above.
An xe2x80x9calkylsulfonyl groupxe2x80x9d is intended to mean the radical xe2x80x94SO2R where R is an alkyl group as defined above.
An xe2x80x9calkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHR where R is an alkyl group as defined above.
A xe2x80x9cdialkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb where Ra and Rb are each independently an alkyl group as defined above.
A xe2x80x9cmercapto groupxe2x80x9d is intended to mean the radical xe2x80x94SH.
An xe2x80x9calkylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SR where R is an alkyl group as defined above.
A xe2x80x9ccarboxy groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH.
A xe2x80x9ccarbamoyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2.
An xe2x80x9caryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORc where Rc is an aryl group as defined above.
A xe2x80x9cheteroaryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORd where Rd is a heteroaryl group as defined above.
An xe2x80x9carylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRc where Rc is an aryl group as defined above.
A xe2x80x9cheteroarylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRd where Rd is a heteroaryl group as defined above.
A xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d is intended to mean a compound that may be converted under physiological conditions or by solvolysis to a compound of formula I or formula X.
A xe2x80x9cpharmaceutically acceptable active metabolitexe2x80x9d is intended to mean a pharmacologically active product produced through metabolism in the body of a compound of formula I or formula X.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formulas I and X. Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I or X in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness and properties of the free acids and bases of compounds of formulas I and X and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines; and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention.
The inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term xe2x80x9coptically purexe2x80x9d is intended to mean a compound which comprises at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity. Preferably, xe2x80x9coptically purexe2x80x9d is intended to mean a compound that comprises at least 90% of a single isomer (80% enantiomeric excess), preferably at least 95% (90% e.e.), more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
Preferably in the above formulas I and X, R1 and R61 are H or F. In the compounds of formula I, preferably M is O.
Preferably R20 in formula I is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18, wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group. More preferably R20 is the alkyl group xe2x80x94C(R41)(R42)NR43R44, wherein R41 and R42 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and R43 and R44 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94NR45R46, xe2x80x94C(O)R45, xe2x80x94C(S)R45, C(O)NR45R46, xe2x80x94C(S)NR45R46, C(O)NR45OR46, xe2x80x94C(S)NR45OR46, xe2x80x94C(O)SR45, xe2x80x94C(O)OR45, C(S)O45, xe2x80x94C(S)SR45, xe2x80x94OR45, xe2x80x94SR45, xe2x80x94C(O)NR45NR46R47, xe2x80x94C(S)NR45NR46R47, xe2x80x94SOR45, xe2x80x94SO2R45, xe2x80x94S(O)NR45R46, xe2x80x94S(O)NR45(OR46), xe2x80x94SO2NR45R46, xe2x80x94SO2NR45(OR46), or xe2x80x94SO3R45, wherein R45, R46, and R47 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or wherein any combination of R41, R42, R43, and R44, together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group. Preferably at least one of R43 and R44 is xe2x80x94C(O)SR45 or xe2x80x94C(O)OR45. Preferably R45 is an alkyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group, or a heteroaryl group, and more preferably a C1-C10 alkyl group.
In the compounds of formula I, preferably D1 and D2 are xe2x80x94OR25, xe2x95x90O, xe2x95x90S, xe2x89xa1N, xe2x95x90NR25, or xe2x80x94NR25R26, wherein R25 and R26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl group, and more preferably D1 and D2 are xe2x95x90O. Preferably, in the compounds of formula I, A1 and A2 are C, CH, S, or S(O), and more preferably A1 and A2 are C.
Preferably, in the compounds of formula I, B1 and B2 are NR17R18, wherein R17 and R18 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group.
In the compounds of formula I and X, preferably Z and Z1 are independently H, an aryl group, or a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23, wherein R21, R22, and R23 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, and R23, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, or Z and Z1, both as defined above, together with the atoms to which they are attached, form a heterocycloalkyl group.
In the compounds of formula X, preferably R66 is xe2x80x94C(O)OR68 or xe2x80x94C(O)S68, wherein R68 is an alkyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group, or a heteroaryl group.
Particularly preferred embodiments of the present invention include the following compounds (1-8, 10, and 11) of formula II: 
wherein R1, R5, R6, R7, R42, R43, and Z are H, R2 is CH2CH2C(O)NH2, and R3, R41, Z1, and R44 are selected from one of the following groups:
(1) R3 is CH2Ph, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(2) R3 is CH2Ph, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(3) R3 is CH2Ph, R41 is CH2CH(CH3)2, Z1 is 
xe2x80x83and R44 is 
(4) R3 is CH2Ph, R41 is CHCH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(5) R3 is CH2Ph, R41 is CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(6) R3 is CH2Ph, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(7) R3 is CH2Ph, R41 is CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(8) R3 is CH2Ph, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
(10) R3 is CH2(p-CH3)Ph, R41 is CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
and
(11) R3 is CH2(p-CH3)Ph, R41 is CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
and pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates thereof.
Another preferred embodiment of the invention includes a compound (9) of formula III: 
wherein R1, R5, R6, R7, R42, R43, and Z are H, R3 is CH2Ph, R2 is CH2CH2C(O)NH2, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
and pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates thereof.
The present invention is still further directed to compositions comprising at least one compound of formula II: 
wherein R1, R5, R6, R7, R42, R43, and Z are H, R3 is CH2Ph, R2 is CH2CH2C(O)NH2, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof, and at least one compound of formula III: 
wherein R1, R5, R6, R7, R42, R43, and Z are H, R3 is CH2Ph, R2 is CH2CH2C(O)NH2, R41 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R44 is 
or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof.
Additional preferred compounds according to the present invention include the following compounds (12 through 34) of formula IV: 
wherein R1, R5, R6, R7, and R42 are H, R2 is CH2CH2C(O)NH2, and R3, Z, Z1, R41, and R44 are selected from one of the following groups:
(12) R3 is CH2(p-CH3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH2Ph, and R44 is 
(13) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(14) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(15) R3 is CH2(p-CF3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(16) R3 is CH2(p-CF3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(17) R3 is CH2(p-CH3)Ph, Z and Z1 together form 
xe2x80x83(where * indicates the point of attachment and the carbonyl group is cis to the R1 group), R41 is CH(CH3)2, and R44 is 
(18) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH2Ph, and R44 is 
(19) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH2CH(CH3)2, and R44 is 
(20) R3 is CH2(p-CH3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(21) R3 is CH2(p-CH3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH2CH(CH3)2, and R44 is 
(22) R3 is CH2Ph, Z is H, Z1 is CO2CH2CH3, R41 is C(CH3)3, and R44 is 
(23) R3 is CH2(p-CH3)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(24) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is cyclohexyl, and R44 is 
(25) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(26) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(27) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(28) R3 is CH2(p-F)Ph, Z is H, Z1 is 
R41 is CH(CH3)2, and R44 is 
(29) R3 is CH2(p-F)Ph, Z is H, Z1 is 
R41 is CH(CH3)2, and R44 is 
(30) R3 is CH2(p-F)Ph, Z is H, Z1 is 
R41 is CH(CH3)2, and R44 is 
(31) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
(32) R3 is CH2(p-F)Ph, Z is H, Z1 is 
R41 is CH(CH3)2, and R44 is 
(33) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH2OH, R41 is CH(CH3)2, and R44 is 
(34) R3 is CH2(p-F)Ph, Z is H, Z1 is CO2CH2CH3, R41 is CH(CH3)2, and R44 is 
and pharmaceutically acceptable prodrugs, salts, active metabolites, or solvates thereof.
The present invention is even further directed to methods of inhibiting picornaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of formula I or X or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof. For example, one can inhibit picornaviral 3C protease activity in mammalian tissue by administering a compound of formula I or X or a pharmaceutically acceptable prodrug, salt active metabolite, or solvate thereof. More particularly, the present invention is directed to methods of inhibiting rhinoviral protease activity.
The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays. An example of a suitable assay for activity measurements is the Antiviral HI-HeLa Cell Culture Assay, described herein.
Administration of the compounds of the formula I or X, or their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include, but are not limited to, oral, nasal, parenteral, topical, transdermal, and rectal.
The inventive compounds of formulas I and X, and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyopholized formulations, such as tablets, powders, capsules, suppositories, suspensions, and aerosols. The pharmaceutical composition may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers may include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of formula I or X or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof) and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of 3C protease activity, by any known method of administering the dose including topical, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean that amount of a compound of formula I or X that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of formula I or X that will correspond to a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, but it can nevertheless be readily determined by one of skill in the art.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus, and includes:
(a) prophylactic treatment in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it;
(b) inhibiting the disease condition; and/or
(c) alleviating, in whole or in part, the disease condition.
The inventive compounds, and their salts, solvates, active metabolites, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described below.
Preferably, the inventive compounds of formula I are prepared by the methods of the present invention, including the general methods shown below. In each of these general methods, R1, R2, R3, R5, R6, R7, R20, R41, R42, Z, and Z1 are as defined above (for formulae I, II, III, IV, and X). 
In General Method I, amino acid A, where P1 is an appropriate protecting group for nitrogen, is converted to carbonyl derivative B, where xe2x80x9cLvxe2x80x9d is a leaving group. Compound B is subjected to a reaction where xe2x80x9cLvxe2x80x9d is replaced by R1 to give derivative C. Derivative C is then transformed into unsaturated product D. Unsaturated compound D is deprotected to give free amine (or salt thereof) E, or modified one or more times at R2, R5, Z, and/or Z1 to give one or more modified D compounds. Modified D is then deprotected to give amine (or salt thereof) E.
Amine E is subsequently subjected to an amide-forming reaction with carboxylic acid F (for which the preparation of representative examples is described below) to give final product G. If protecting groups were used on any R groups (R1, R2, R3, R5, R6, R7, and/or R20), on Z and/or on Z1, product G is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified G.xe2x80x9d
In General Method II, amine E, which can be prepared as described in General Method I, is subjected to an amide-forming reaction with carboxylic acid H, where P2 is an appropriate protecting group for nitrogen, and where at least one of R3 and R6 is H, to give final product I. Carboxylic acid H can be prepared as a mixture of diastereomers as described in Harbeson, S. L., Rich, D. H., J. Med. Chem. 1989, 32, 1378, the disclosure of which is incorporated herein by reference. The P2 protecting group, along with any additional protecting groups that were used on any R groups (R1, R2, R3, R5, R6, R7, and/or R41), on Z and/or on Z1, is subsequently deprotected and/or further modified to yield xe2x80x9cdeprotected or modified I.xe2x80x9d
In General Method III, optically active lactone J, where P2 is an appropriate protecting group for nitrogen, is transformed by a two-step procedure (basic hydrolysis and subsequent oxidation) into carboxylic acid K. Lactone J can be prepared by the method described in General Method IV below and by many literature methods including, but not limited to, those described in the following: (a) Herold, P.; Duthaler, R.; Rihs, G.; Angst, C., J. Org. Chem. 1989,54, 1178; (b) Bradbury, R. H.; Revill, J. M.; Rivett, J. E.; Waterson, D., Tetrahedron Lett. 1989, 30, 3845; (c) Bradbury, R. H.; Major, J. S.; Oldham, A. A.; Rivett, J. E.; Roberts, D. A.; Slater, A. M.; Timms, D.; Waterson, D., J. Med. Chem. 1990, 33, 2335; (d) Wuts, P. G.; Ritter, A. R.; Pruitt, L. E., J. Org. Chem. 1992, 57, 6696; (e) Jones, D. M.; Nilsson, B.; Szelke, M., J. Org Chem. 1993, 58, 2286; (f) Pxc3xa9gorier, L.; Larchevxc3xa9que, M., Tetrahedron Lett. 1995, 36, 2753; (g) Dondoni, A.; Perrone, D.; Semola, M. T., J. Org. Chem. 1995, 60, 7927, all of which are incorporated herein by reference. Carboxylic acid K is not isolated in pure form, but is subjected to an amide-forming reaction with amine E, which can be prepared as described in General Method I, to provide final product L. The P2 protecting group, along with any additional protecting groups that were used on any R groups (R1, R2, R3, R5, R7, and/or R41), on Z and/or on Z1, is subsequently deprotected and/or further modified to yield xe2x80x9cdeprotected or modified L.xe2x80x9d
Lactone J may be prepared in optically active form by General Method IV (see: (a) Herold, P.; Duthaler, R.; Rihs, G.; Angst, C., J. Org. Chem. 1989, 54, 1178; (b) Bradbury, R. H.; Revill, J. M.; Rivett, J. E.; Waterson, D., Tetrahedron Lett. 1989, 30, 3845; (c) Bradbury, R. H.; Major, J. S.; Oldham, A. A.; Rivett, J. E.; Roberts, D. A.; Slater, A. M.; Timms, D.; Waterson, D., J. Med. Chem. 1990, 33, 2335). A xcex3,xcex4b-unsaturated carboxylic acid M, which incorporates R41, is transformed into the corresponding acid chloride (not shown). This acid chloride is subjected to an amide-forming reaction with a chiral amine or a chiral oxazolidone to provide derivative N (in which X1 is a chiral amine or a chiral oxazolidone). Compound N is subsequently deprotonated, and the resulting enolate is diastereoselectively alkylated with an electrophile corresponding to R3 to provide compound O. This material is then subjected to a halolactonization reaction to provide halo-lactone P, in which H1 is Br or I. Halo-lactone P is subsequently transformed into azide Q, and this material is then converted into lactone J, where P2 is an appropriate protecting group for nitrogen. 
xcex3,xcex4-Unsaturated carboxylic acid M may be prepared by General Method V (see: Herold, P.; Duthaler, R.; Rihs, G.; Angst, C., J. Org Chem. 1989, 54, 1178). An aldehyde R, which incorporates R41, is coupled with vinylmagnesium bromide to give alcohol S. Alcohol S is then transformed into xcex3,xcex4-unsaturated carboxylic acid M by a three step procedure as follows: (i) treatment with diethyl malonate and catalytic Ti(OEt)4 at 160xc2x0 C. for 1 hour, (ii) at 190xc2x0 C. for 4 hours, and (iii) hydrolysis with ethanolic KOH at reflux. 
Carboxylic acid K also may be prepared by General Method VI (see: Hoffman, R. V., Tao, J., Tetrahedron, 1997, 53, 7119, which document is entirely incorporated herein by reference). An amino acid T, which incorporates R41 and where P2 is an appropriate protecting group for nitrogen, is transformed into xcex2-ketoester U. Compound U is deprotonated, and the resulting anion is condensed with triflate V, which incorporates R3. The coupling product thus obtained is treated with trifluoroacetic acid to provide ketoester W, and this material is subsequently hydrolyzed to afford carboxylic acid K. If basic hydrolysis results in epimerization, ketoester W can be transesterified [allyl alcohol, Ti(Oi-Pr)4] and subsequently deprotected under neutral conditions [Pd(PPh3)4, morpholine] to give carboxylic acid K. Triflate V, in turn, may be prepared from the corresponding alcohol by treatment with trifluoromethanesulfonic anhydride and 2,6-lutidine. 
Lactone J also may be prepared by General Method VII (see: (a) Askin, D., Wallace, M. A., Vacca, J. P., Reamer, R. A., Volante, R. P., Shinkai, I. J. Org. Chem. 1992, 57, 2771 (b) McWilliams, J. C., Armstrong, J. D., Zheng, N., Bhupathy, M., Volante, R. P., Reider, P. J., J. Am. Chem. Soc. 1996, 118, 11970; each of these documents is entirely incorporated herein by reference). An amino acid T, which incorporates R41 and where P2 is an appropriate protecting group for nitrogen, is transformed into epoxide X (single diastereomer) by the method described in: Luly, J. R., Dellaria, J. F., Plattner, J. J., Soderquist, J. L., Yi, N., J. Org. Chem. 1987, 52, 1487, the disclosure of which is entirely incorporated herein by reference. Alternatively, X may be prepared from T as a mixture of diastereomers as described in the xe2x80x9cExamplesxe2x80x9d section of this document. Epoxide X is condensed with the anion derived from compound Y, which incorporates R3 and in which X2 is a chiral auxiliary [including (1S,2R)-1-aminoindan-2-ol acetonide] to afford coupling product Z. If X was utilized as a mixture of diastereomers, the diastereomer of Z depicted below is purified from other Z isomers (if any) produced in the coupling reaction. This material is subsequently cyclized under acidic conditions to provide lactone J. Compound Y may be prepared from the corresponding carboxylic acid (not shown) by the method outlined in: Askin, D., Wallace, M. A., Vacca, J. P., Reamer, R. A., Volante, R. P., Shinkai, I., J. Org. Chem. 1992, 57, 2771.
Suitable protecting groups for nitrogen are recognizable to those skilled in the art and include, but are not limited to benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-methoxybenxyloxycarbonyl, trifluoroacetamide, and p-toluenesulfonyl. Suitable protecting groups for oxygen are recognizable to those skilled in the art and include, but are not limited to xe2x80x94CH3, xe2x80x94CH2CH3, tBu, xe2x80x94CH2Ph, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2OCH2CH2Si(CH3)3, and xe2x80x94CH2CCl3. Other examples of suitable protecting groups for nitrogen or oxygen can be found in T. Green and P. Wuts, Protective Groups in Organic Synthesis (2nd ed. 1991), the disclosure of which is incorporated herein by reference.
Suitable leaving groups also are recognizable to those skilled in the art and include, but are not limited to, Cl, Br, I, sulfonates, O-alkyl groups, 
Other examples of suitable leaving groups are described in J. March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure (4th ed. 1992) at pages 205, 351-56, 642-43, 647, 652-53, 666, 501, 520-21, 569, 579-80, 992-94, 999-1000, 1005, and 1008, the disclosure of which is incorporated herein by reference.